A5073413438- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- Synthesis and Biological Evaluation
- HIV/AIDS drug development and treatment
- Malaria Research and Control
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Parasites and Host Interactions
- Enzyme Structure and Function
- Crystallization and Solubility Studies
- Enzyme function and inhibition
- X-ray Diffraction in Crystallography
- Protein Kinase Regulation and GTPase Signaling
- Drug Transport and Resistance Mechanisms
- Carbohydrate Chemistry and Synthesis
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- Bioactive Compounds and Antitumor Agents
- Cancer therapeutics and mechanisms
- Synthesis and Catalytic Reactions
- Calcium signaling and nucleotide metabolism
- Inflammatory mediators and NSAID effects
- Organoselenium and organotellurium chemistry
- Antibiotics Pharmacokinetics and Efficacy
- Chemical Synthesis and Analysis
University of Dundee
2012-2023
Wellcome Centre for Anti-Infectives Research
2018-2023
Wellcome Trust
2012-2018
Fexinidazole, a drug in clinical testing for African sleeping sickness, shows potential as an oral treatment another neglected tropical disease.
N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report optimization of high throughput screening hit (1) to give lead molecule DDD85646 (63), has potent activity against enzyme (IC50 = 2 nM) and T. brucei (EC50 in culture. The compound good oral pharmacokinetics cures rodent models peripheral HAT infection. This provides an excellent tool validation NMT as well valuable...
Drug discovery pipelines for the "neglected diseases" are now heavily populated with nitroheterocyclic compounds. Recently, bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates treatment of visceral leishmaniasis. Using a combination quantitative proteomics whole genome sequencing susceptible drug-resistant parasites we putative NAD(P)H oxidase activating nitroreductase (NTR2). Whole revealed that deletion single cytosine in gene NTR2...
There is an urgent requirement for safe, oral and cost-effective drugs the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), approved drug multi-drug resistant tuberculosis, a potent inhibitor Leishmania donovani both in vitro vivo. Twice-daily dosing at 30 mg kg-1 5 days resulted sterile cures mouse model VL. Treatment with lower doses revealed U-shaped (hormetic) dose-response curve greater parasite suppression 1 than 3 (5 or 10 day dosing). Dosing confirmed...
The antiplasmodial activity, DMPK properties, and efficacy of a series quinoline-4-carboxamides are described. This was identified from phenotypic screen against the blood stage Plasmodium falciparum (3D7) displayed moderate potency but with suboptimal physicochemical properties poor microsomal stability. screening hit (1, EC50 = 120 nM) optimized to lead molecules low nanomolar in vitro potency. Improvement pharmacokinetic profile led several compounds showing excellent oral P. berghei...
ABSTRACT The novel nitroimidazopyran agent ( S )-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and vivo is currently phase II clinical trials for (TB). In contrast to M. , where R inactive, we report here that both enantiomers of PA-824 show parasiticidal Leishmania donovani the causative visceral leishmaniasis (VL). leishmania-infected macrophages, 6-fold more active than )-PA-824. Both des-nitro analogues are underlining importance nitro group...
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor TbNMT. Although this compound represents excellent lead, poor central nervous system (CNS) exposure restricts its use to hemolymphatic form (stage 1) disease. With clear clinical need new drug treatments HAT that address both and CNS stages disease, chemistry...
RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for parasite survival make it an attractive drug target development new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor (6-PGDH), third enzyme pentose phosphate pathway. However, this compound does not trypanocidal activity due to its poor membrane permeability. Consequently, we previously reported prodrug...
Crystallography has guided the hybridization of two series Trypanosoma brucei N-myristoyltransferase (NMT) inhibitors, leading to a novel highly selective series. The effect combining selectivity enhancing elements from pharmacophores is shown be additive and led compounds that have greater than 1000-fold for TbNMT vs HsNMT. Further optimization hybrid identified with significant trypanocidal activity capable crossing blood-brain barrier. By using CF-1 mdr1a deficient mice, we were able...
The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard care for VL suffers from multiple issues and there a limited pipeline new candidate drugs. As such, clear unmet medical need to identify treatments. This paper describes optimization phenotypic hit against Leishmania donovani, major causative organism VL. key challenges were balance solubility metabolic stability while...
Abstract Previously reported pyrrolones, such as TDR32570, exhibited potential antimalarial agents; however, while these compounds have potent activity, they suffer from poor aqueous solubility and metabolic instability. Here, further structure–activity relationship studies are described that aimed to solve the developability issues associated with this series of compounds. In particular, modifications lead pyrrolone, involving replacement a phenyl ring piperidine removal potentially...
We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR not present adult epidermis of mice. Targeted expression and activation by a selective synthetic agonist sufficient to induce an inflammatory skin disease resembling Several signalling pathways dysregulated psoriasis are replicated this model, suggesting contributes pathogenesis. Thus, inhibition might harbour therapeutical potential. Since has pleiotropic functions...
The lack of information regarding the mechanisms action (MoA) or specific molecular targets phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report results our orthogonal genetic, molecular, and biochemical studies determine MoA novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that displays promising activity against Trypanosoma brucei Leishmania donovani .
There is an urgent need for new, brain penetrant small molecules that target the central nervous system second stage of human African trypanosomiasis (HAT). We report a series novel indoline-2-carboxamides have been identified as inhibitors Trypanosoma brucei from screening focused protease library against in culture. describe optimization and characterization this series. Potent antiproliferative activity was observed. The demonstrated excellent pharmacokinetic properties, full cures 1...
The clinical use of mefloquine (MQ) has declined due to dose-related neurological events. Next generation quinoline methanols (NGQMs) that do not accumulate in the central nervous system (CNS) same extent may have utility. In this study, CNS levels NGQMs relative MQ were measured and an early lead chemotype was identified for further optimization. plasma brain twenty five, 4-position modified determined using LCMS/MS at 5 min, 1, 6 24 h after IV administration (5 mg/kg) male FVB mice....
Abstract The enzyme N ‐myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around pyrazole sulfonamide series, derived high‐throughput screen. Herein we describe work thiazolidinone benzomorpholine scaffolds that were also identified in An X‐ray crystal structure hit Leishmania major NMT showed compound...
A screen of a focused kinase inhibitor library against Trypanosoma brucei rhodesiense led to the identification seven series, totaling 121 compounds, which showed >50 % inhibition at 5 μm. Screening these hits in T. b. proliferation assay highlighted three compounds with 1H-imidazo[4,5-b]pyrazin-2(3H)-one scaffold that sub-micromolar activity and excellent selectivity MRC5 cell line. Subsequent rounds optimisation exhibited good vitro drug metabolism pharmacokinetics (DMPK) properties,...
N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. NMT as druggable treatment of HAT in both stages 1 and 2 disease. report on use reported DDD85646 (1) starting point design class potent, brain penetrant inhibitors NMT.
Trypanosomatid parasites are the infectious agents causing Chagas disease, visceral and cutaneous leishmaniasis human African trypanosomiasis. Recent work of others has implicated an aldo-keto reductase (AKR) in susceptibility resistance Trypanosoma cruzi to benznidazole, a drug used treat disease. Here, we show that TcAKR homologues related brucei Leishmania donovani do not reductively activate monocyclic (benznidazole, nifurtimox fexinidazole) or bicyclic nitro-drugs such as PA-824....
In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in P. berghei mouse model malaria. The most promising compound (13) showed reduction parasitemia 96% when dosed at 30 mg/kg orally once day for 4 days It also demonstrated rapid rate clearance erythrocytic stage falciparum SCID an ED90 11.7 orally. Unfortunately, is potent inhibitor...
Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000–65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy, and unsuitable dosing options. need for new urgent led to collaboration between the Drugs Neglected Diseases initiative (DNDi), GlaxoSmithKline (GSK), University of Dundee. An 8-hydroxynaphthyridine was identified start point, an early compound demonstrated weak efficacy mouse model VL but...
Abstract Screening of the Sigma–Aldrich Library Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei , causative agent African sleeping sickness, resulted in identification a number compounds with selective antiproliferative activity over mammalian cells. These included (+)‐(1 R ,2 )‐U50488, weak opioid agonist an EC 50 value 59 n M as determined our T. vitro assay reported previously. This paper describes modification key structural elements U50488 to investigate...